Ticagrelor, a trade name, with the chemical name being (1S,2S,3R,5S)-3-(3-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-ylamino)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol, is a chemical having the structural formula as shown in Formula (I) below:

The chemical is a cyclopentyl-triazolo-pyrimidine, a novel and selective anticoagulant developed by AstraZeneca (UK), and the first reversibly binding adenosine diphosphate (ADP) antagonist targeting the P2Y12 receptor. This chemical is able to reversibly act on the purinoceptor 2 subtype P2Y12 on the vascular smooth muscle cell (VSMC). This chemical has a significant inhibitory effect on platelet aggregation caused by ADP, and is able to improve the acute coronary disease symptoms effectively. Since this chemical's antiplatelet effect is reversible, it is particularly applicable to those patients who need anticoagulant therapy prior to surgery. Compared with Clopidogrel, a competitor, Ticagrelor is superior in terms of clearly reducing symptoms of myocardial infarction, stroke or cardiovascular death, and is thus an anticoagulant with a promising future.
In the prior art, the patent literatures related to Ticagrelor synthesis methods include U.S. Pat. No. 6,525,060, US20030148888, WO2011017108, CN102659815A, CN102675321A, CN102149716A, WO2012085665, WO2012138981, WO2012138981, etc. These existing patents/patent applications have disclosed many synthesis methods and processes for preparing Ticagrelor.
Chinese patent application No. CN102149716A (AstraZeneca, the original research company) discloses a synthesis route for preparing Ticagrelor (I), comprising the steps of using 2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta[d]-1,3-dioxolalkenyl-4-yl]oxy]ethanol of Formula (I-1) and 4,6-dichloro-2-propylthiopyrimidine-5-amine as the starting materials to get a key intermediate (I-2); ring closing of the intermediate (I-2) in the presence of an appropriate alkali metal nitrite to get an intermediate (I-3); reacting the intermediate (I-3) with an appropriate salt of (1R,2S)-REL-2-(3,4-difluorophenyl)cyclopropylamine; and finally removing the protecting group.

Based on published information, the route of synthesis described in patent applications CN102149716A and WO0192263 is the existing industrial production process developed by the original research company to prepare bulk pharmaceutical chemicals of Ticagrelor. The synthesis of the key intermediate (I-2) is the key control point of the process. The reaction requires a high temperature, as well as an oxygen-free environment and a certain pressure condition for a long time. Thus, the reaction is limited due to certain equipment. Since the reaction is carried out under high temperature and pressure conditions for a long time, there is also a potential danger in terms of industrial production.
Chinese patent application No. CN102675321A discloses a synthesis route for preparing Ticagrelor (I), comprising the steps of using 2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta[d]-1,3-dioxolalkenyl-4-yl]oxy]ethanol (II-1) protected by an alkoxy or a silyl reagent and 4,6-dichloro-2-propylthiopyrimidine-5-amine as the starting materials to prepare a key intermediate (II-2); ring closing of the intermediate (II-2) in the presence of an appropriate alkali metal nitrite to prepare an intermediate (II-3); reacting the intermediate (II-3) with an appropriate salt of (1R,2S)-REL-2-(3,4-difluorophenyl)cyclopropylamine; and finally removing the protecting group.

This method has the same characteristics as those of the original research company's patent application No. CN102149716A and WO0192263 in terms of the synthesis strategy. The defects of the method lie in that the reaction still requires a high temperature, as well as an oxygen-free environment and a certain pressure condition for a long time; the resulting intermediate is of low purity and dark color, making it troublesome to purify the final product and difficult to remove the color; and the total yield of the process is quite low.
U.S. Pat. No. 6,525,060 discloses a synthesis route for preparing Ticagrelor (I), comprising the steps of reacting 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine with (3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta[d]-1,3-dioxolalkenyl-4-ol (III-1) to get an intermediate (III-2); reducing the intermediate (III-2) in an iron powder/acetic acid system; ring closing of the resulting product in the presence of a nitrite; and finally carrying out a series of reactions, including ammoniation, bromination and a substitution reaction.

The method has a prolonged route, wherein due to the strong electron-withdrawing effect of the nitro group, the chlorines on positions 4 and 6 of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine are of high activity, and readily react with the amino group and the hydroxyl group of the molecule of (III-1). The reaction system is typically complicated, and the resulting intermediate is difficult to purify. The entire route involves many reactions under harsh conditions, such as bromination, ammoniation and the application of butyl lithium reagent. In view of all of these, together with other disadvantages, it is clear that this route is not suitable for industrial production.
Patent application No. CN102875537A discloses a synthesis route for preparing Ticagrelor of Formula (I), comprising the steps of reacting 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine with a protected amino alcohol of Formula (IV-2) to get an intermediate of Formula (IV-3); reducing the nitro group of the intermediate (IV-3) under the catalyst of palladium-carbon to get an intermediate of Formula (IV-4); ring closing of the intermediate (IV-4) in the presence of a nitrite to get an intermediate of Formula (IV-5); reacting the intermediate (IV-5) with a chiral cyclopropylamine to get an intermediate of Formula (IV-6); reducing the intermediate (IV-6) with sodium borohydride under the catalyst of sodium bromide to get an intermediate of Formula (IV-7); and finally removing the propylidene protecting group under an acidic condition.

This route has similar problems as those of U.S. Pat. No. 6,525,060. It is difficult to control the selectivity of the reaction in the first step. In addition, the intermediate of Formula (IV-2), an amino-acid ester, is naturally of poor stability due to severe intermolecular amino-ester exchange reaction, resulting in less industrial feasibility. Moreover, during the hydrogenation of the intermediate of Formula (IV-3) under the catalyst of palladium-carbon, the chlorine atom on the pyrimidine ring tends to be removed by hydrogenation, and the resulting contaminant is difficult to remove completely, but finally brought to the product, resulting in high difficult purification of the product, low yield and high cost. Accordingly, this route is not suitable for industrial production.
International Patent Application No. WO2012138981 discloses a synthesis route for preparing Ticagrelor of Formula (I), comprising the steps of starting from 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine by a classic aromatic amine protection method to get 4,6-dichloro-2-(propylthio)-5-formamidopyrimidine (V−1); reacting (V−1) with a chiral amino acid of Formula (V-2) in the presence of an appropriate base to get an intermediate of Formula (V-3); removing the formyl group and the hydroxyl protecting group on the side chain of the intermediate (V-3) under an appropriate acidic condition to get an intermediate of Formula (V-4); reacting the intermediate (V-4) with an alkali metal nitrite to get an intermediate of Formula (V-5); reacting the intermediate (V-5) with a chiral cyclopropylamine to prepare an intermediate of Formula (V-6); and finally reducing the intermediate (V-6) with sodium borohydride.

This route has an advantage of conciseness. The adoption of formyl group protection is able to activate the chlorine atom in the molecule of aminopyrimidine, thereby making a mild condition for the substitution reaction. However, the adoption of an acidic system to remove the formyl group in the subsequent process makes it inevitable to remove the propylidene protecting group on the side chain, resulting in great polarity of the subsequent intermediates, which is unfavorable to the purification of the intermediates. Moreover, the presence of several exposed hydroxyl groups reduces the stability of the intermediate (V-5), such that intermolecular autoreaction is easy to carry out, thereby making it difficult to purify the final product.